Type 2 diabetes mellitus constitutes an enormous health burden in the United States, and despite the[unreadable] increasing prevalence of this disease there are still major gaps in understanding the underlying causes.[unreadable] Increasing evidence indicates that type 2 diabetes ensues when beta-cell secretion is insufficient for insulin[unreadable] needs, and that the development of insulin resistance accelerates this process. Obesity is a common cause of[unreadable] insulin resistance and this connection is mediated in part by increased levels of fatty acids in the circulation[unreadable] of overweight individuals. Recent studies of cultured cells suggest that elevations of fatty acids may also be[unreadable] detrimental to insulin secretion and islet growth. Moreover, these studies suggest a differential effect among[unreadable] fatty acids, with saturated but not monounsaturated fatty acids leading to beta-cell damage. These interesting[unreadable] findings have not been confirmed in vivo. Thus, high circulating levels of fatty acids could contribute to the[unreadable] increased demand for, and decreased supply of, insulin that are the core problems leading to diabetes. In[unreadable] the first cycle of this program project we demonstrated that ad libitum intake of a diet containing 20% of[unreadable] calories as butter fat- a high saturated fat diet- caused rats to get obese, insulin resistant, and[unreadable] hyperinsulinemic. They also developed glucose intolerance indicating that their beta-cell response was[unreadable] inadequate to compensate for their increased insulin requirements. The overall goal of this application is to[unreadable] determine whether increased fat content in the diet leads to beta-cell dysfunction and whether the specific types[unreadable] of fatty acids consumed are important in this process. The central hypothesis guiding this application is that[unreadable] the intake of high amounts of saturated fat in the diet impairs islet function and the ability to compensate for[unreadable] insulin resistance. We will test this hypothesis by completing three specific aims: i) To determine the effects[unreadable] of short- and long-term exposure to diets high in saturated or monounsaturated fatty acids on glucose[unreadable] metabolism; 2) To determine the effects of dietary saturated fatty acids on beta-cell adaptation to increased[unreadable] demand; 3) To determine the effects of varying ambient concentrations of mono- and saturated-fatty acids[unreadable] on islet/p-cell function and lipid content. Completion of this project will extend a body of compelling in vitro[unreadable] work to intact animals and provide important new information regarding the effect of diet on beta-cell function[unreadable] and glucose tolerance. These translational studies are highly relevant to human disease and could form the[unreadable] basis for clinical studies aimed at modifying diabetes risk.